Many fungal secondary metabolites are of industrial interest, such as antibiotics, while others are undesirable compounds such as mycotoxins. Overexpression of mtfA enhances production of fungal compounds with applications in the medical field, and overexpression or impaired mtfA expression decreases the production of compounds that negatively affect health/agriculture/economy such as mycotoxins.
Numerous fungal secondary metabolites, also denominated natural products, have beneficial biological activities that can be use in the medical field, including antibiotics and antitumoral drugs among others.
Other fungal natural products, such as mycotoxin, are detrimental for human and animal health and negatively impact agriculture causing economic losses.
Species of the genus Aspergillus produce numerous secondary metabolites (Adrio and Demain, 2003; Reverberi et al., 2010; Brakhage and Schroeckh, 2011), including compounds with beneficial effects, such as antibiotics and other molecules with application in the medical field. Other secondary metabolites produce by these organisms are detrimental, such as mycotoxins (Bennett and Klich, 2003). Aspergillus nidulans, a model filamentous fungus studied for more than fifty years, produces the mycotoxin sterigmatocystin (ST). ST and the carcinogenic compounds called aflatoxins (AF), produced by related species such as A. flavus, A. parasiticus, and A. nomiusi (Cole and Cox, 1981), are both synthesized through a conserved metabolic pathway (Payne and Yu, 2010; Sweeney and Dobson, 1999; Payne and Brown, 1998) where ST is the penultimate precursor. The genes responsible for ST/AF biosynthesis are clustered. Within the clusters, the regulatory gene aflR encodes a transcription factor that acts as a specific cluster activator (Keller and Hohn, 1997; Yu et al., 1996; Fernandes et al., 1998).
Aspergillus nidulans also produces the beta-lactam antibiotic penicillin and the antitumoral compound terraquinone.
In fungi secondary metabolism regulation and is often found to be govern by genetic mechanisms also controlling asexual and sexual development (Calvo et al., 2002). One of this main common regulatory links is the global regulatory gene veA, first described to be a developmental regulator in A. nidulans (Kim et al., 2002). In 2003 we describe for the first time the connection between veA and the synthesis of numerous secondary metabolites, including ST (Kato et al., 2003). Absence of the veA gene in A. nidulans prevents aflR expression and ST biosynthesis. VeA also regulates the production of other metabolites, including penicillin (Kato et al., 2003). In other fungi, veA homologs also regulate the synthesis of penicillin in Penicillium chrysogenum (Hoff et al., 2010) as well as cephalosporin C in Acremonium chrysogenum (Dreyer et al., 2007). Furthermore, veA also regulates the biosynthesis of other mycotoxins, for example AF, cyclopiazonic acid and aflatrem in Aspergillus flavus (Duran et al., 2007; Calvo et al., 2004; Duran et al., 2009), trichothecenes in F. graminerum (Merhej et al., 2011), and fumonisins and fusarins in Fusarium spp, including F. verticillioides and F. fujikuroi (Myung et al., 2011; Niermann et al., 2011).
veA is extensively conserved in Ascomycetes (Myung et al., 2011). Most of the studies on the veA regulatory mechanism of action have been carried out using the model fungus A. nidulans. It is known that KapA α-importin transport the VeA protein to the nucleus, particularly in the dark, a condition that favors ST production (Stinnett et al., 2007, Araujo-Bazan et al., 2009). In the nucleus, VeA interacts with several proteins such as the light-responsive protein FphA, which interacts with the LreA-LreB. FphA, LreA and LreB also have influence fungal development and mycotoxin production (Purschwitz et al., 2008). While FphA negatively regulates sexual development and the synthesis of ST, the LreA and LreB proteins play the opposite role. In the nucleus VeA also interacts with VelB and LaeA (Bayram et al., 2008; Calvo, 2008; Bayram and Braus, 2012). LaeA, a chromatin-modifying protein is also required for the synthesis of ST and other secondary metabolites (Reyes-Dominguez et al., 2007; Bok and Keller, 2004). Deletion of velB decreases and delayed ST production, indicating a positive role in ST biosynthesis (Bayram et al., 2008; Bayram and Braus, 2012).
In addition to its role as global regulator of development and secondary metabolism, VeA is also require for normal plant pathogenicity by several mycotoxigenic species, such as A. flavus (Duran et al., 2009), F. verticillioides (Myung et al., 2012), F. fujikuroi (Wiemann et al., 2010), and F. graminearum (Merhej et al., 2011). Deletion of veA homologs in these organisms results in a decrease in virulence with a reduction in mycotoxin biosynthesis.